Alkanoylthio and pyrazolo androstane derivatives



United States Patent 3,094,522 ALKANOYLTI-IIO AND PYRAZOLO ANDROSTANE DERIVATIVES Arthur A. Patchett, Metuchen, and Glen E. Arth, Cranford, N.J., and Harvey Schwam, Woodside, N.Y., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed July 25, 1961, Ser. No. 126,509

24 Claims. (Cl. 260-2395) This invention is concerned generally with novel steroids and processes of preparing the same. More particularly, it relates to novel compounds having the following structure:

and wherein R stands for -i J 01' "CHF and wherein R is hydrogen or alkyl when R is and R is hydrogen or acyl when R is CH and wherein X is halogen. This invention also concerns closely related compounds, and in particular the 7a-alkanoylthio and the pyrazolo derivatives, and the A and A -analogues of the above compounds.

The above described compounds possess useful therapeutic properties as aldosterone inhibitors. These novel steroids block the salt-retaining effects of aldosterone and other salt retaining steroids so as to be useful in the treatment of diseases such 'as congestive heart failure, nephrosis and cirrohis of the kidney in which aldosterone secretion is increased V In preparing our novel chemical compounds the starting material utilize-d is 3u-acetoxy-lo-pregnene-l1,20- dione (see Flow Sheet A). This compound is heated with hydroxylamine hydrochloride and an organic base such as pyridine to give 3u-acetoxy-16-pregnene-11,20- dione 20-oxime. The latter compound is treated with an aryl sulfonyl halide such as p-acetylaminobenzenesulfonyl chloride and an organic base followed by acid hydrolysis and reactylation to form 3a-acetoxy-5B-androstane-11,l7-dione. This forms the 3a-acetoxy-5fl-androstane-l1,17-dione 17-oxime on heating with hydroxylamine hydrochloride and an organic base.

The 3a-acetoxy-518-androstane-11,17-dione 17-oxime is converted to 3a-acetoxy-l7fl-nitro-5fi-androstane-115-01 by treating with N-bromosuccinimide in aqueous dioxane under oxidizing conditions, for example, with vigorous stirring over an extended period, to form the 3a-acetoxy- 17a-bromo-17/8-nitro-5B-androstane-ll-one. The latter compound is then converted into 3a-acetoxy-175-nitro- 5Bandrostane-l 15-01 by reacting with sodium borohydride in aqueous tetrahydrofuran solution.

The 3a acetoxy-l7fl-nitro-5p-androstane-llfi-ol is re- "Ice acted with methyl acrylate in the presence of base to give 3a-acetoxy-17a-[2'-methoxycarbonylethyl]-17 3-nitro- SB-androstane-llfi-ol. The latter compound is treated with methane sulfonyl chloride in the presence of an organic base such as pyridine to afiord 3a-acetoxy-17u- [2'methoxycarbonylethyl]-17fl-nitro 9(11) 5,8 androstene. Reduction of 3u-acetoxy-17a-[2-methoxycarbon ylethyl]-17;8-nitro-9(15)-5/8-androstene with zinc dust in acid solution forms 3-(3a-acetoxy-l7B-amino-9'(11')- 5'B-androstene-l7'a-yl)-propionic acid lactam. The latter compound is converted into 3-(l7B-amino-3a-hydroxy- 9( 11)-5fi-androstene-l7'a-yl) -propionic acid lactam, for example, by heating with an auqeous methanolic solution of alkali metal bicarbonate. The 3-(17fl-amino-3'a-hydroxy-9'(11)-5;3-androstene-17a-yl)-propionic acid lactam is oxidized to 3-(17'fi-amino-9(11)-5B-androstene- 3-one-17a-yl)-propionic acid lactam, for example, with chromium trioxide in the presence of an organic base such as pyridine. The 3-(17p-amino-9'(11)-5',8-androstene-3'-one-l7a-yl)-propionic acid lactam is converted into 3-( 17';8-4a1rrrino-"4,9"(11)-andro-stadiene-3 -one-l7uyl)propionic acid lactam by treatment sequentially with bromine in hydrogen bromide and acetic anhydride and then with a mixture of lithium bromide and lithium carbonate in an organic solvent.

' 17a-yl)-propionic acid lactam is converted into 3-(3'ahydroxy-l7,8-methylamino-9'( 11')-5fi androstene- 17ayl)-propionic acid lactam by reaction first with dihydropyran in the presence of an acidic catalyst to form 3-(17'5- amino-3 'a-hydroxy-9( 1 1 -5 '13-androstene- 17a-yl) -propionic acid lactam 3u-tetrahydropyranyl ether. The latter compound is methylated, for example, using methyl iodide and sodium hydride and then treated with acid to give 3- (3 'a-hydroxy-17 9 methylamino-9( 1 1 -5 'B-androstene- 17'a-yl) -pnopionic acid lactam. The 3-( 3'a-hydroxy-17'B- methylarnino-9(11)-5fi-androstene-l7'a-yl) propionic acid lactam is then oxidized to 3-(l7fl-methylamino-9- 1 1) -5'fl-androstene-3-one-17a-yl) -propionic acid lactam using chromium trioxide in pyridine. The 3-(17'B inethylamino-9' 1l)-5;9-androstene-3-one l7a-yl) -propionic acid lactam is converted into 3-(17'B-methylamino- 4,9"(ll')-androstadiene-3'-one-17u yl) propionic acid l'actam by treatment sequentially with bromine in a hydrogen bromide-acetic anhydride reagent and then with a mixture of lithium bromide and lithium carbonate in an organic solvent.

The 3 l7'B-amino-3'a-hydroxy8 1 1 -5 'B-androstene- 17'a-yl)-propionic acid lactam is reduced with lithium aluminum hydride, in a solvent such as dioxane to give 3a-hydr0xy-9(11)-5/8-androstene-17-spiro-2'- (1 2') 8- pyrrolidene (see Flow Sheet B). The latter compound is converted into a 3 a-acyloxy-9'( 1 1 -5,8-androstane-17-spiro- 2-(1'-2')fi-1'-acylpyrrolidene by treating with an acylating agent, tag. a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride or tertiary butyl acetyl chloride; a lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or 3u-hydr0xy-9(1-1)-5fl androstene-17-spiro-2-(1'-2')B- 1'-acylpyrrolidene can be converted to 4,9'(1l)-androstadriene-3-one-17-spiro-2'-(1'-2)fl-1 acylpyrrolidene in the same manner as that indicated above for the conversion of 3-(17fl-amino-3'a-hydroxy-9'( 11)-5fi androstene-lT-ayl)-propionic acid lactam to 3-(17'fi-arnino-4',9(11')- androstadiene-3-one-17a-yl)-p-ropionic acid lactarn.

The 3-(17fl-arnino-4',9( 11')-androstadiene-3-one-17'- a-yl)-propionic acid lactam, 3-(17B-methyla1nino-4,9'- (11)-androstadiene-3-one-17'a-yl)-propionic acid lactarin and 4,9 l l -androstadiene-3-0ne-17-spiro 2'( 1 -2) -1 acylpyrrolidene may be converted into the corresponding 3 (17'13-amino-9a-fiuoro-4'-androstene-3',l1-dione-17- a-yD-propionic acid lactam, 3-(9'a-fluoro-l7flaniethylamino 4-androstene-3',11'-dione-17'a-yl)-propionic acid lactarn, or 9a-fluoro-4 androstene-3,l1-dione-17-spiro-2- (1-2) ,B-1-acylpyrrolidene (see Flow Sheet C) by react ing first with N-bromo'succinimide in dioxane to fonrn the corresponding 9a-bromo-1lfi-hydroxy-derivative; heating the latter compound with potassium acetate in absolute ethanol to obtain the corresponding 9,8,l1/3-oxide; then converting the 95,11/3-o'xid into the corresponding 9ahalo-11 fi-hydroxy-der'ivative and in particular the 9dfluoro-'1lfi hydroxy-derivative, forf example, by treating with anhydrous hydrogen fluoride in tetrah'ydrofuran; and finally oxidizing the 9ix-fluo'ro-1lfi-hydroxy-derivative to obtain the corresponding 9oi-fluoro-1LketO-ctimpoiind. 9o: fluoro-4-androstene 3,l 1-dione-1"7-spiro'-2-( l'-2)flpyrrolidene may beprepared by mineral acid hydrolysis of 9d-fluoro-4w'androstene-3, l l-dione -l7-spiro-2"-(1'-2),B-1'- acylpyrrolidene, especially when the acyl group is readily hydrolyzed, as for example, when the acyl group is forrnyl.

The 3 17'p-aminoeammo-4'-andro stene-s',11'-dione-17'a-yl)-propionic acid lactain, 3-(9' -flnaro-17'p' methylamino 4"-androstene-3,11'-dione 17'a-yl)-propionic acid lactam and 9a-fluoro'-4+androstene-3,1l-dione- 17-spiro-2'-(l'-2)fl-lacylpyrfolidene are converted into the corresponding A -analogues on treatment with se= leniuni dioxide (see Flow Sheet D).

The 3 (17'fi amino-9oz-fiuoro 4'-androstene-3',11'-dione-17'a-yl) propionic acid :lactarn, a- 9'a-fiuoro-17'pmethylamino 4'-andro'ste ne 3',l1' dione 17'a-yl)-propionic acid 'lactam and 9ot-fluoro 4-androstene-3Jl-dione- 17-spiro-2'-( 1 2),B-1'-acylpyrrolidene are converted into the corresponding 3-(7balk-anoylthio-l7'B-amino-9afluoro-4'-androstene-3 ',1 1'-dione -17'ot-yl) fp'ropioni'c acid lactam, 3- 7 'walkano ylthio-9 admire-17 ,B methy1'a inin'o- 4"-androstene-'3,l1'-dione 17'bi yl)-propionic acid lactatn and 7e2-alkanoylthio-4-androstene 3,11-dione 17-spirci-2'- (1 2)B-1'-acylpyrrolidene by dehydrogenation with chloranil to form the corresponding M' -analogue and then reacting the latter compound with a thioalkanoie acid. Among the radicals comprehended by the expression alkanoyl are for-myl, acetyl, propionyl, butyryl, valeryl, hexanoyl, he'p'ta'noyl, octanoyl and branched-chain isomers thereof, said alkanoyl radicals being the acyl (radicals of alkanoic acids containing fewer than nine carbon atoms. p

the corresponding 3-(17'fi-amino-[3',2'-c]pyrazo1o4-androstene-l1-one-17'u-yl)-pr0pionic iacid lactam, 3-(175- methylarnino [3,2' c]pyrazolo-4-androstene-11'-onel7a-yl)-propionic acid lactam and 9a-fluoro-[3,2-]PYrazolo 4-androstene-3,11-dione-17-spiro-2'-(1-2);3-1'-acylpyrrolidene by first reacting with an alkyl formate and strong base in an inert atmosphere to form the corresponding 2-hydroxymethylene derivative, and then reacting the latter compound with hydrazine, or a monosubstituted hydrazine, to give the corresponding pyrazolo compound, which is exemplified in Flow Sheet D as compound'28, K

The structure of the pyrazolo-compound designated in the flow sheet is based upon an interpretation of data according to the state of the art presently known to organic chemists. However, it is to be understoodthat no part of the specification will be materially defective if it shoiild later be established that the correct structure of any of these compounds with respect to the position of the double bonds and the R substituent in the pyrazolering-is isoijneric to the structure shown, and in particular ifthe following structure exists:

wherein R stands for R is hydrogen or alkyl when R is hydrazines, butylhydrazines, 19 hydro ethylhydr'azine,

cycloal kylhydr'aziiie'sj arylhydrazines sueh as phehylhy drazine, 0-, 611-, and phalophenylhydrazines, o-, 111:, and p-tolylh'ydra'z'iries, 6-, in, and p-alkoxyphenylhydrazines'; 0-, m-, and pmitroplienylhydrazines, l-hyd'ra'z'inonaphthalene; 2-hydrazinopyridine, 3'-hydra zinopyridine any: drazinopyridine, 4-hydrazinopyridine oxide, and -2"-hy-' drazinopyrir'nidine; and aralkylhydrazines such as Befizyt hydrazine and phenyl'ethylenehydrazine.

Flow Sheet A 111; cm o=o =Noii Ac-N wherein Ac represents acyl.

Flbw Sheet C Ac-N 2a 25 wherein R stands for R is hydrogen or alkyl when R is and'R is acyl when R is and x is halogen.

Flow Sheet D wherein R stands for or -CH3 R is hydrogen or alkyl when R is i and R is acyl when R is CI-I R is hydrogen, alkyl, cycloalkyl, aryl or aralkyl, and wherein X is halogen.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation.

EXAMPLE 1 A solution of 192 g. of 3a-acetoxy-l6-pregnene-11,20-dione, 45 g. of hydroxylamine hydrochloride and 204 ml. of pyridine in 770 ml. of ethyl alcohol are refluxed for 0.5 hour. Then 195 ml. of hot Water is added to the hot reaction mixture and the solution is allowed to cool slowly to room temperature. The crystalline precipitate is collected on a filter, washed with 400 ml. of 50% methanol-water solution and air dried to yield 187 g. of crude 3a-acetoxyl6-pregnene-1l,20-dione 20-oxime.

EXAMPLE 2 A solution of 215 g. of crude 3a-acetoxy-16-pregnene- 11,20-dione 20-oxime in 580 ml. of dry pyridine is cooled to between 5 and C. To this is added dropwise and with stirring 258 g. of p-acetylaminobenzenesulfonyl chloride in 515 ml. of pyridine. This addition requires one and one-quarter hours. Stirring is continued at O-5 C. for one hour, and then at 10-20 C. for three hours. One liter of water is added, and then 1.4 liters of mixed solvent is distilled from the mixture under reduced pressure. A solution of three hundred and fifty ml. of concentrated sulfuric acid in 2.6 liters of water is added and this mixture is heated and stirred vigorously at 80 C. for one hour. The brown oil is extracted four times with ether, Washed once with aqueous sodium bicarbonate and then two times With water. After distillation of the dried ether, the residue is made crystalline by trituration with petroleum ether. Filtration affords 168 g. of a mixture of 3u-hydroxy-S/S-androstane-l1,17-dione and 3a-acetoxy- 5 fl-androstane-l 1,17-dione.

A solution consisting of 74 g. of the above mixture, 360 ml. of pyridine and 80 ml. of acetic anhydride is heated on the steam bath for twenty minutes. Water is added cautiously to the cooled mixture to afford 75 g. of 3a-acetoxy- 5,8-androstane-11,17-dione.

EXAMPLE 3 A solution of 75 g. of 3wacetoxy-iB-androstane-11,17- dione, 17.3 g. of hydroxylamine hydrochloride and 500 ml. of pyridine is heated on a steam cone at 90 C. for 2.5 hours. the solution is cooled and diluted with 300 ml. of water. The precipitate is collected on a filter, rinsed well with water and air dried to yield 68 g. of 3m-acetoxy- SB-androstane-l1,17-dione-17-oxime. A sample for analsis melts at 190-193" C. after crystallization from methanol.

EXAMPLE 4 To a slurry of 110 g. of N-bromosuccinirnide in 350 ml. of dioxane and 350 ml. of Water there is added simultaneously 65 g. of 3ot-acetoxy-5B-androstane-11,17-dione-l7- oxime in 700 ml. of dioxane and 61 g. of potassium bicarbonate in 350 m1. of Water. The mixture is stirred for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed successively with a saturated ferrous sulfate solution (2 times), water, 10% sodium bisulfite (2 times) and again with water. After drying over anhydrous sodium sulfate, the ethyl acetate is removed under vacuum leaving a solid residue. This is dissolved in 1.8 liters of an 80% tetrahydrofuranwater solution and 31 g. of sodium borohydride is added over a 40 minute period with vigorous stirring. The mixture is stirred for 2.5 hours and g. of hydroxylamine hydrochloride in 1.2 liters of water is added slowly. The solution is extracted with ether and the ether extract is washed successively with Water, ferrous sulfate, water, sodium bisulfite and water. Concentration of the ether extract afiords 13 g. of 3a-acetoxyl7 3-nitro-5B-androstane-lLB-ol. Chromatography over acid washed alumina yields an additional 7 g. of product. The analytical sample has a M.P. of ISO-183 C.

EXAMPLE 5 To 19.2 g. of 3a-acetoxy-17 3-nitro-518-androstane-l1B- 01 in 290 ml. of methyl acrylate and 145 ml. of t-butanol there is added 29 ml. of methanolic tetramethylammonium hydroxide. The solution is left overnight in a stoppered flask and it is then poured into ml. of 2.5 N hydrochloric acid and an equal volume of ice. The organic materials are extracted into ether which is washed once with 50 ml. of a saturated potassium bicarbonate solution and two times with water. The dried solvent is evaporated in vacuo until crystallization begins. The crystals are collected on a filter, washed with cold ether, and air dried to yield 20.7 g. of 3a-acetoxy-l7a-[2-methoxycarbonylethyl]-17B-nitro-5fi-androstane-llp-ol, M.P. 214- 220" C. A sample for analysis, after crystallization from ethyl acetate, melts at 220-222 C.

EXAMPLE 6 A solution consisting of 17.1 g. of 3a-aC6tOXY-l7ot-[2'- methoxycarbonylethyl]-17,3-nitro-5fl-androstane 11p 01, 102 ml. of dimethylformamide and 51 ml. of collidine is cooled to +10 C. Twenty ml. of methanesulfonylchloride is added and the reaction flask is immersed immediately in an oil bath maintained at 35 C. After 20 minutes the reaction mixture is poured into 1.5 liters of cold water and the solid is collected by filtration. Crystallization from methanol yields 11.7 g. of 3u-acetoxy-17a-[2- methoxycarbonylethyl]-l7,B-nitro-9(11) 5,8 androstene, M.P. 127-130 C. The mother liquor is chromatographed over acid washed alumina and the 50% petroleum ether-ether eluates yields an additional 2.8 g. The analytical sample from methanol has a M.P. of 129- 130 C.

EXAMPLE 7 To 12.2 g. of 3a-acetoxy-17a-[2'-methoxycarbonylethyl]-l7,8-nitro-9(ll)-5fl-androstene in 300 ml. of glacial acetic acid there is added 12.2 g. of zinc dust in small portions over a 65 minute period. After 1 hour, 12.2 g. more of zinc is added and the mixture is stirred for 18 hours. The mixture is filtered and the filtrate is evaporated under reduced pressure. Dilution with water and filtration yields 9.74 g. of 3-(3'a-acetoxy-17'fi-amino-9'(11)Sfl-androstene-17'a-yl)-propionic acid lactam, M.P. 230-235 C. (crystal change at 220 C.). A sample for analysis melts at 238-240 C. after crystallization from ethyl acetate.

EXAMPLE 8 To a solution of 3 g. of 3-(3'a-acetoxy-17'fi-amino- 9(11')-5'fi-androstene-lTa-yl)-propionic acid lactam in 94 ml. of methanol there is added a solution of 6.5 g. of potassium bicanbonate in 36 ml. of water. The solution is refluxed for four hours, cooled, poured into water and extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is crystallized from ethyl acetate to yield 2.71 g. of 3-(175- amino 3'18 hydroxy 9(l1) 5'5 androstene 17'ec yl)-propionic acid lactam, M.P. 179-183 C.

EXAMPLE 9 A solution of 3.5 g. of 3-(l7 3-arnino-3fi-hydroxy- 9'(1l)-5[i-androstene-l7'a-yl)-propionic acid lactam in 20 :ml. of pyridine is added slowly with stirring to a pyridine-chromic acid complex prepared from 3.5 g. of chromium trioxide and 20 ml. of pyridine. After 18 hours. at room temperature the dark brown solution is poured into water and extracted two times with ethyl acetate.

11 "mean-Y1 acetate is-washe'dtwotimeswith dilute hydrochloric-acid, threetii'nes withwater and dried over 'so diur'i'rsulfate. The solvent is evaporated'in vacuo and the residue is crystallized from ethyl acetate to yield 2.412 g. of 3 -'(17'fi amino-9'(11) 5fi-androstene-3-one-17otylyprcpiunie acid lactam, M.P. 245250 C. The anasample is crystallized from methanol, M.P. 255- 258" EXAM'PLE 10 A solution of 1.26 g-. of 3-(l7fi-amino-9(11)-5'fiandtostene-S-one-'17'a-yl)-propionic acid lactam, 21 ml. of'chloroform', 5 m1. of glacial acetic acid and 0.5 ml. of HBr-acetic anhydride reagent is stirred at C. The latter solution is prepared by adding 0.5 ml. of 48% hydrobromic -acid to 2 ml. of cold acetic anhydride. To the reaction mixture there is added dropwise over a onehou'r'period 14 ml. of glacial acetic acid containing 670 mg.- of bromine and 2 ml. of the HBr-acetic anhydride reagent. After stirring'for an additional forty-five minutes,- the reaction is'quen'che'd by the addition of 4 g. of acetate. The mixture is poured into water, extracted with-chloroform and the chloroform layer is washed with Water, dried over sodium sulfate and conceiit f'ated invaciios' V I The crude product 1.6 g.) is heated in an oil bath at 120 C. for two hours with 30 ml. of dimethylformamide, 116 :g. of lithium bromide and 1.6 g. of lithium carbonate. The reaction mixture is cooled, diluted with water and extracted ethyl acetate. The organic layer is washed with water, dried'over sodiumsulfate and concentrated in vacuo. Crystallization from ethyl acetate yields 560 mg. of 3=(17/3-amino-4,9(11)-androstad1- ene- 3'-one'-17'w-y1)-propionic acid lactam, M.P. (decomp.) 288-294" C. The analytical sample is crystallized-frommethanol, (decomp.) 294298 0., ultraviolet absorption k 238 mu, 6 15,640.

EXAMPLE 11 Five-hundred mg. of 3-(l7'18 amino-3'fi-hydroxy-9' (11)-5'fl=androstene=17ot=yl) propionic acid lactam 1s reacted at'room temperature for eighteen hours with 50 m1. of dry dihydropyran and 150 mg. of p-toluenesulfonyl chloride. This mixture is their diluted With sodium bicarbonate solution'and a crystalline precipitate of the yl)-propionic acidlactam 3B-tetrahydropyranyl other is collected.

' Asolutio'n is prepared-of 250 mg. of this tetrahydropyranyl ether in 8-m1. of dimethylformamide and 16 ml. of benzene. Eight ml. of benzene is distilled off to insure dryness. After the addition of 80 mg. of sodium hydride; a yellow anion developed. Two ml. of methyl iodide is added and the mixture-is stirred overnight under nitrogen'and then refluxed for one hour. The mixture is diluted with benzene, washed with Water, dried and evaporated to yield crude 3-(3ot-hydroxy-17fl-methylamino 9(11)-5'B-androstene-17u-yl)-propionic acid lactarn 3'5- tetrahydropyranyl ether.

The reversal of the ether at C-3 is accomplished by. adding the steroid to a mixture of 20 mg. of p-toluene sulfonic acid in 10 ml. of ethanol. After eighteen hours at room temperature, some of the ethanol is removed on the rotator, water is added and the product is extracted into ethyl acetate. The solvent is washedwith dilute sodium bicarbonate, dried and evaporated. Recrystallization of the residue from methylene chloride-ether yields 3-(3'cchydroxy 173- methylamino 9'(11)-5/3-androstene-' I7'a-YD-PI'OP1OI11C acid lactam.

EXAMPLE 12 A solution of 3.5 g. of 3-(3'a-hydroxy-17fl-methylamino-9( 11')-5',8-androstene 17'a-yl)-propionic acid lactam in ml; of pyridine is added slowly with stirring to a pyridine chromic'acid complex prepared from 3.5 g. of chromium trioxide and 20 ml. of pyridine. After 18 hours at room temperature the dark brown solution is poured 12 into water and extracted two times with ethyl acetate. The ethyl acetate is washed two times with dilute hydrochloric acid, three times with water and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is crystallized from ethyl acetate to give 3-(17/3- hydrobromic acid to 2 ml. of cold acetic anhydride. To

the reaction mixture there is added dropwise over a onehour period 14 ml. of glacial acetic acid containing 670 mg. of bromine and 2 ml. of the HBr-acetic anhydride reagent. After stirring for an additional forty-five minutes, the reaction is quenched by the addition of 4 g. of potassium acetate. The mixture is poured into water, extracted with chloroform and the chloroform layer is washed with water, dried over sodium sulfate and concentrated in vacuo.

The crude product (1.6 g.) is heated in an oil bath at C. for two hours with 30 ml. of dimethylformamide, 1.6 g. of lithium bromide and 1.6 g. of lithium carbonate. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated in vacuo. Crystallization from ethyl acetate yields 3- (17',8 methylamino 4,9( 1 1) androstadiene 3 one- 17a-yl)-propionic acid lactam.

EXAMPLE 14 One gram of 3-('17'fl-amino-3'fl-hydroxy-9'(11')-5';8- androstene-17u-yl)-propionic acid lactam is refluxed with three grams of lithium aluminum hydroide in 400 ml. of purified dioxane for ninety hours. Ether and saturated aqueous sodium potassium tartrate are added carefully to the cooled solution. This mixture is filtered through Supercel (an infusorial earth) and then concentrated in vacuo to remove most of the dioxane. Dilute sodium hydroxide is added and the desired amine is brought into ethyl acetate with several extractions. Removal of the washed and dried solvent leaves 3ot-hy droxy-9(11)-5 3- androsten'e-l 7-spiro-2-( 1-2 ,B-pyrrolidene.

EXAMPLE 15 The diac'etylation of 250 mg. of 3ot-hydroxy-9(1l)-5fiandrostene l7 spiro-2-(1'-2),9-pyrrolidene is accomplished with 2.5 ml. of acetic anhydride and 2.5 ml. of pyridine. This mixture is heated on the steam bath under nitrogen for one and one half hours. It is then taken to dryness on the rotating evaporator and the residue is crystallized from methylene chloride-ether to give 3w acetoxy 9(11) 5e androstene 17 spiro 2' (1- 2 6- 1 -acetylpyrrolidene.

The diformylation of 250 mg. of 3u-hydroxy-9(l1)-5B- androstene 17 spiro-2-(1-2)p-pyrrolidene is accomplished by adding the compoundat 0 C. to 2 ml. of acetic anhydride in 5 ml. of 98% formic acid. The mixture is allowed to come to room temperature and after eighteen hours, excess reagent is removed at room temperature on the rotating evaporator. The residue is crystalliz'ed from methylene chloride-ether to give 3ot-formyloxy 9(11) 5B androstene- 17 spiro 2' (1' 2')fi- 1 -formylpyrrolidene.

' EXAMPLE 16 To a solution of 3 g. of 3ot-acetoxy-9(11)-5}3-androstene'-17-spiro-2'-(1-2')fi-Y-acetylpyrrolidene in 94 ml. of methanol there is added a solution of 6.5 g. of potassium bicarbonate in 36 ml. of water. The solution is refluxed for four hours; cooled, poured into water and extracted with ethyl acetate. The ethyl acetate solution is Washed with water, dried over anhydrous sodium sulfate 13 and concentrated in vacuo. The crude product is crystallized from ethyl acetate to yield 3u-hydroxy-9(11)-5;3-androstene-17-spiro-2-( 1 '-2' B-1-acetylpyrrolidene.

In accordance with the above procedure, but starting with the corresponding 3u-formyloxy-9(11)-5fi-androstene17-spiro-2-( 1-2')e-1'-formylpyrrolidene, there is obtained the corresponding 3a-hydroxy-9(11)-5fi-andro' stene-17-spiro-2-( 1-2' ;3-1-formylpyrrolidene.

EXAMPLE 1? A solution of 3.5 g. of 3a-hydroxy-9(11)-5/8-androstene-17-spiro-2-(1'-2')fl-1-acetylpyrrolidene in 20 m1. of pyridine is added slowly with stirring to a pyridinechromic acid complex prepared from 3.5 g. of chromium trioxide and 20 ml. of pyridine. After 18 hours at room temperature, the dark brown solution is poured into water and extracted two times with ethyl acetate. The ethyl acetate is washed two times with dilute hydrochloric acid, three times with water and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is crystallized from ethyl acetate to yield 9(11)-5}9-androstene3one-17-spiro-2-( 1-2 S-pyrrolidene.

'In'accordance with the above procedure, but starting with 3a-hydroxy 9(11) 5B androstene-17-spiro-2-(1'- 2)B-1-formylpyrrolidene in place of 3a-hydroxy-9(11)- 5 3 androstene 17 spiro 2' (1 2);8 1' acetylpyrrolidene there is obtained the 9(11)-55-androstene-3- one-17-spiro-2'-( 1 -2 [3-1 -formylpyrrolidene.

EXAMPLE 18 A solution of 1.26 g. of 9(11)-5fl-androstene-3-one-17- spiro-2(1'-2),B-1'-acetylpyrrolidene, 21 ml. of chloroform, 5 ml. of glacial acetic acid and 0.5 ml. of HBracetic anhydride reagent is stirred at C. The latter solution is prepared by adding 0.5 ml. of 48% hydrobromic acid to 2 ml. of cold acetic anhydride. To the reaction mixture there is added dropwise over a one-hour period 14 ml. of glacial acetic acid containing 670 mg. of bromine and 2 ml. of the HBr-anhydride reagent. After stirring for an additional forty-five minutes, the reaction is quenched by the addition of 4 g. of potassium acetate. The mixture is poured into Water, extracted with chloroform and the chloroform layer is washed with water, dried over sodium sulfate and concentrated in vacuo.

The crude product (1.6 g.) is heated on an oil bath at 120 C. for two hours with 30 ml. of dimethylformamide, 1.6 g. of lithium bromide and 1.6 g. of lithium carbonate. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated in vacuo. Crystallization from ethyl acetate yields 4,9- (11) androstadiene 3 one 17 spiro 2 (1' 2)fl l-acetylpyrroliclene.

In accordance with the above procedure, but starting with the 9(ll)-5,8-androstene-3-one-17-spiro-2-(1-2)13- 1'-acetylpyrrolidene, there is obtained the corresponding 4,9(11) androstadiene 3 one 17 spiro 2 (1'- 2' B-1'-formylpyrrolidene.

EXAMPLE 19 0.71 milliliters of 0.2 N perchloric acid is added with stirring to a suspension of 200 mg. of 3-(17,B-amino4,9- (1 l')-androstadiene-3-one-17 'ct-Y1)PFOP1OH1C acid lactam, 135 mg. of N-bromosuccinimide and 4 ml. of dioxane at C. This mixture is left in the refrigerator for three and one-half hours and is then diluted carefully with water until a precipitate occurs. The crystals are collected on a filter, washed two times with water and dried to yield 176 mg. of crude 3-(17'fi-amino-9'a-bromo-1l'B- 'hydroxy-4-androstene-3-one-17a-yl)-propionic acid lactam.

To a suspension of 176 mg. of the above compound in 5 ml. of dry methanol there is added 0.5 ml. of a 1 N sodium methoxide solution, and the mixture is stirred at room temperature for minutes. The reaction is terminated by the addition of glacial acetic acid and ice-water. After cooling, the crystalline precipitate is collected, washed with water and dried in vacuo to yield 120 mg. of 3-(17'fi-arnino-9,11' epoxy-4'-andros-tene-3 one-17%;- yl)-propionic acid lactam. Two crystallizations from ethyl acetate affords the analytical sample, M.P. (decomp) 282286 C. ultraviolet absorption at x 243 mu, 514,240.

A hydrogen fluoride solution is prepared at ---60 C. from 10.4 g. of anhydrous hydrogen fluoride, 14.3 ml. of tetrahydrofuran and 7.5 m1. of chloroform. One and one-half cc. of this solution is kept at -60 C. and to it is added 54 mg. of 3-(l7fi-amino-9,l1-epoxy-4'-andro stene-3-one-l7'a-yl)-propionic acid lactam in 0.75 ml. of chloroform likewise chilled at 60 C. The reaction mixture is maintained at -40 C. for two and one-half hours and then it is added to a well agitated mixture of aqueous potassium carbonate, chloroform and ice. The organic layer is washed two times with water, dried over sodium sulfate and concentrated in vacuum. Crystallization from ethyl acetate yields 30 mg. of 3-(l7' 3-amino- 9a-fluoro-1l,B-hydroxy-4'-androstene 3' one-17'a-yl)- propionic acid lactam, M.P. (decomp) 310-320 C. with ultraviolet absorption at A 238 ma, 6 15,980.

A solution of 400 mg. of 3-(17'B-amino-9a-fluoro-l 1'5- hydroxy-4'-androstene-3-one-17a-yl)-propionic acid lactam in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 m1. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 3-(17j3-amil'10'9'd-fil1OI'O- 4-androstene-3,11-dione-17a-yl)-propionic acid lactam.

In accordance with all of the above procedures, but

starting with 3-(17'5-methylamino-4',9'(1l')-androstadiene-3-one-l7'a-yl)-propionic acid lactam, or 4,9-(1l)-androstadiene-3-one-l7-spiro-2'-(1'-2)18-1'-acylpyrrolidene in place of 3-(17'B-amino-4,9(11') androstadiene-3'-onel7'a-yl)-propionic acid lactam, there is obtained the corresponding 3-(9a-fluoro-17'j8-methylamino-4'-androstene- 3',11'-dione-17'a-yl)-propionic acid lactam, 9a-flu0r0-4- androstene 3,11-dione-17-spiro-2'-(1'-2)B-1-acylpynrolidene. 4 A solution of 250 mg. of 9ot-fluoro-4-androstene-3,11- dione-l7-spiro-2'-(1-2)B-1'-formylpyrrolidene in 10 cc. of ethanol containing 2 cc. of concentrated hydrochloric acid is refluxed for 4 hours. Evaporation of the solvent under reduced pressure leaves the hydrochloride of 9a-fiuoro-4- androstene 3,11 dione-17-spiro-2-(1-2)p-pyrrolidene. The hydrochloride is treated with alkali in an inert solvent and is chromatographed on basic alumina to yield the purified free base.

EXAllIPLE 20 To mg. of 3-(17',8-amino-9a-fluoro-4'-androstenc- 3,11'-dione-l7a-yl) propionic acid lactarn in 5 ml. of tbutanol and 0.1 ml. of acetic acid is added 50 mg. of selenium dioxide. The mixture is refluxed under nitrogen for 18 hours; then 50 mg. of selenium dioxide is added and the mixture is refluxed for an additional 24 hours. The mixture is filtered and the filtrate evaporated to dryness. The residue is extracted with ethyl acetate and the extract is washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, Water, dilute hydrochloric acid and water, and then dried over magnesium sulfate. The extract is treated with activated charcoal and then concentrated to dryness. Crystallization of the residue from a mixture of acetone and ether gives 3-(17'fi-amino-9'a-fluoro4,4-androstadiene-3 ,l ldione-17'a-yD-propionic acid lactam.

In accordance with the above procedure, but starting with 3-(9a-fluoro-17,B-methylamino-4-androstene-3', l 1- dione-l7'a-yD-propionic acid lactam or 9a-fluoro-4-androstem-3,1l-dione-l7-spiro-2'-(1'-2')p-l acetylpyrrolidene inplace of 3-(l7fl-aminor9a-fluoro-4-androstene-3',l1'- dione-l7'a-yD-propionic acid lactam, there is obtained the corresponding 3-(9'a-fluoro-l7'p methylamino-1',4'-androstadiene-3",ll-dione-l7'u-yl)-propionic acid lactam or 9a-fluoro-1,4-androst2idiene-3,11 dione-l7-spiro-2-(l-2') p-1'-ace.tylpyrrolidene.

EXAMPLE 21 A solution of 200 mg. of 3-(17-amino-9'a-fiu0ro-4- androstene-3',1l'-dione-17'a-yl)-propionic acid lactam and 400 mg. of chloranil in 30 ml. of t-butanol are refluxed overnight. The mixture is then taken down to dryness in vacuo and chromatographed on silica gel. Elution with chloroform-acetone (1:1) aflords 3-(l7B-amino-9wfluoro- 4,6'-androstadiene-3',11-dione-17'a-yl) propionic acid lactam.

To 10"- ml. of freshly distilled thioacetic acid there is added 150 mg. of 3-(1736-arnino-9a-fluoro-4,6'-androstadiene3',ll-dione-17u-yl)-propionic acid lactam. This solution is heated on the steam bath under nitrogen for one-half hour and excess thioacet-ic acid is blown'oif with nitrogen. The residue is taken up in ethyl acetate and washed with sodium bicarbonate and Water. Removal of the dried solvent and trituration with methanol gives 3- (7u-acetylthiol7'fl-amino-9'a-fluoro-4'-androstene-3,1 1'- dione-17oz-yD-propionic acid lactam.

In accordance with the above procedures, but starting with the 3-(9'a-fluoro-l7p methylamino-4-androstene- 3',11-dione-17'a-yl)-propionic acid lactam or 9ot-fluoro-4-v androstene 3,11 dione-l7-spiro-2'-( l'-2)fl-l"-acetylpyrrolidene inplaceof 3-(17,8-amino-9'u-fluoro-4'-andro stene-3 ,11 -dione-17'a-yl)-propionic acid lactam there is obtained as product the corresponding 3-(7a-acetylthio- 9'0: fluoro-l7,B-methylamino-4-androstene-3',11-dionel7"u-yl)-propionic acid lactam or 7a-acetylthio-4-andro- Ste ne-3,1l-dione-17-spiro-2'-(1-2)fl-1'-acetylpyr-rolidene.

EXAMPLE 22 A suspension of 610 mg. of 3-(17'p-amino-9'a-fluoro- 4-androstene-3',11',-dione-17'u yl) propionic acid lactam in 50 ml. of dry benzene is stirred in a nitrogen atmosphere with 1 ml. of ethyl formate and 450 mg. of a suspension of about 54% sodium hydride in mineral oil at room temperature for 19 hours. Stirring is continued for 2 more hours after the addition of 1 ml. of ethyl formate and 350 mg. of sodium hydride. The reaction mixture is chilled in an icebath and acidified with an excess of an aqueous solution of sodium dihydrogen phosphate. The layers are separated and the aqueous phase is extracted with ether, with ethyl acetate and with methylene chloride. The combined organic layers are extracted with sodium bicarbonate to remove impurities. The product is then extracted into a 2% aqueous solution of sodium hydroxide. Acidification of the alkaline extracts with dilute hydrochloric gives a product which is taken up in methylene chloride. The solution is filtered and evaporated to dryness, to give 3-(l7B-amino-9'a fluoro 2 hydroxymethylene 4 androstene-3',11'-di0ne-l7a-yl)-propionic acid lactam.

A suspension of 610 mg. of 3-(l7li-amino-9'a-fluoro- 2' hydroxymethylene 4 androstene 3,11' dione- 17'a-yl) -propionic acid lactam in 50 ml. of dry benzene is stirred in a nitrogen atmosphere with 1 ml. of ethyl formate and 450 mg. of a suspension of about 54% sodium hydride in mineral oil at room temperature for 19 hours. Stirring is continued for 2 more hours after the addition of 1 ml. of ethyl formate and 350 mg. of sodium hydride. The reaction mixture is chilled in an icebath and acidified with an excess of an aqueous solution of sodium dihydrogen phosphate. The layers are 1'6 separated and the aqueous phase is extracted with ether, with ethyl actate andwith methylene chloride. The combined organic layers are extracted with sodium bicarbonate to remove impurities. The product is then extracted into a 2% aqueous solution of sodium hydroxide. Acidification of the alkaline extracts with dilute hydrochloric acidgives a product which is taken up in methylene chloride. The solution is filtered and evaporated to dryness, to give 3-(l7B-amino-[3,2-c]pyrazolo-4-androstene-ll'-one-17'ot yl) propionic acid lactam.

In accordance with the above procedures, but starting with 3 (9'a-fluoro-17' 8-methylamino-4'-androstene- 3,11-dione-17'a-yl)-propionic acid lactam or 9u-fluoro- 4-androstene-3,11-dione 17 spiro-2 '-(1-2),8-l'-acetylpyrrolidene in place of 3-(17,8-amino-9'oc-fluoro-4-andro stene-3,11-dione-17a-yl)-propionic acid lactam there is obtained as product the corresponding 3-(17',8-methylamino [3',2'-c]pyrazolo-4'-androstene-1l one 17'uyl)-propionic acid lactam or 9a-fiuoro-[3,2-c]pyrazolo- 4-androstene-3,11-dione-17-spiro 2' (1'2'),B-l'-acetylpyrrolidene.

Various changesand modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. A compound of the formulal Rs-k/ -Rz in which in which R is selected from the group consisting of lower alkyl, hydroxyalkyl, cycloalkyl, phenyl, tolyl, alkoxyphenyl, nitrophenyl, naphthyl pyridyl, N-oxidopyridyl, pyrimidyl, benzyl and phenethyl,

R is selected from the group consisting of hydrogen and, together with R a pyrazolo group as defined above,

X is selected fro mthe group consisting of hydrogen, halogen and, together with Y, 9 (11) double bonds and epoxy groups,

Y is selected from the group consisting of keto oxygen, fl-hydroxyl and, together with X, 9 (11) double bonds and epoxy groups, and the dotted lines in the 1, 2, and 3 and 5, 6 positions show that each of these bonds is selected from the group consisting of single and double bonds.

3. Ba-acetoxy 17a-['2.-methoxycarbonylethyl] nitro-9(11)-5fi-androstene. 

1. A COMPOUND OF THE FORMUAL- 